December, 1988]

© 1988 The Chemical Society of Japan

Bull. Chern. Soc. Jpn., 61, 4435—4437 (1988)

4435

Synthesis and Structure of the Diterpenoid Peucelinendiol J o a q u í n R. MORAN, Victoria ALCAZAR, a n d M a n u e l GRANDE*

Department of Organic Chemistry, F. C. Químicas, University of Salamanca, 37008 Salamanca, Spain (Received March 19, 1988) The synthesis of peucelinendiol has been carried out starting from geraniol, and using as a key intermediates the anion of phenylthiogeraniol and (—)-geraniol epoxide obtained by the Sharpless procedure. Its structure was stablished as (6S,7fl)-7-hydroxymethyl-2,6,10,14-tetramethylpentadeca-2,9,13-trien-6-ol. Isopeucelinendiol, epipeucelinendiol, and epiisopeucelinendiol were also synthesized.

Some years a g o we isolated from Magydaris panacifolia (Umbelliferae) a new diterpenoid n a m e d magydardiendiol, 1 ' for w h i c h the irregular isoprenoid structure 1 was recently proposed. 2 ' T h e structure of this diol seems to be t h e result of a h e a d to head c o u p l i n g of two m o n o t e r p e n e units, i.e. two geranyl u n i t s linked t h r o u g h Q - C / a n d C 3 -C 4 '. A l t h o u g h the head to head c o u p l i n g is n o r m a l i n the biogenesis of triterpenoids a n d carotenoids, it is q u i t e u n u s u a l in the case of lower terpenoids. We have only found two m o r e diterpenoids with a head to head skeleton, namely digeranyl 3 ' a n d peucelinendiol 2. 4) Moreover the Q - C 2 ' u n i o n between isoprenoid chains, q u i t e u n c o m m o n , is also present for instance i n lavandulol a n d in tetraterpenes like that o n e isolated from Elodea canadensis.^ We were interested i n peucelinendiol, because it could be a biogenetic precursor of 1, a n d the fact that neither the absolute n o r the relative stereochemistry for 2 were given, encouraged us to accomplish the total asymmetric synthesis of peucelinendiol. Peucelinendiol can be envisaged as the product from the attack of a n i o n A o n the epoxide B, b o t h materials easily available from geraniol. T h e synthesis of each one of the two possible diastereomers for 2 can be done if the suitable cis or trans epoxide B is used as starting material. T h e n u c l e o p h i l e A can be p r e p a r e d as a m a g n e s i u m derivative, a c u p r a t e or a sulfur-stabilized a n i o n . However the h i g h nucleophilicity of stabilized sulfur

Chart

1.

anions allows to carry o u t the displacement reactions u n d e r very m i l d conditions a n d formation of secondary by-products (rearrangement, allylic attack, halohydrine formation-•) is minimized. Also good yields are reported i n the reaction of allylic sulfur-stabilized a n i o n s a n d epoxides. 6 ' 7 1 We chose the geranyl phenyl sulfide 4, as a synthetic equivalent of carbanion A. T r e a t m e n t of geraniol with 2,4-dinitro-l-fluorobenzene 8 1 yielded the a r o m a t i c ether 3, w h i c h o n reaction w i t h p o t a s s i u m benzenethiolate gave the expected allylic sulfide 4 whose physical properties are in good agreement with those reported. 6 ' It is k n o w n that the hydroxyl g r o u p in allylic alcohols can induce the selective epoxidation of the /3,ydouble b o n d i n the presence of other olefins. Furthermore, it is possible the asymmetric epoxidation of allylic alcohols w i t h i-butyl hydroperoxide, ( + ) diethyl tartrate a n d titanium(IV) isopropoxide. 9 1 We used this m e t h o d to prepare the epoxidic substrate B. In o u r h a n d s , the asymmetric e p o x i d a t i o n of geraniol proceeded smoothly to yield the optically active geranyl epoxide 5 in 80% e.e. T h e free hydroxyl g r o u p of 5 is n o t c o m p a t i b l e w i t h the strong basic conditions needed to the c o u p l i n g w i t h the a n i o n A, so that protection either w i t h butyl vinyl ether, or w i t h methyl isopropenyl ether was used, to give the respective acetal derivatives 6 or 7 i n h i g h yield. Metallation of the allylic sulfide 4 (BuLi, D A B C O / T H F — 25 °C), followed by addition of the protected alcohol epoxide 6 gave i n a fast a n d clean reaction, after deprotection, a single m i x t u r e of the p h e n y l t h i o isomers 8. Desulfuration of this material was accomplished either with Raney Ni, or with L i / N H 3 / E t 2 N H . In b o t h cases mixtures of constitutional isomers 2 a n d 9 were obtained. A l t h o u g h the ratio 2 / 9 was h i g h e r w h e n the desulfurization was carried o u t with L i / N H 3 / E t 2 N H , the p r o d u c t d i s t r i b u t i o n was difficult to c o n t r o l . C h r o m a t o g r a p h y o n S i 0 2 allowed us to separate b o t h c o m p o u n d s . T h e physical constants of the diol w i t h the three trisubstituted double bonds were in good agreement w i t h the previously reported for peucelin e n d i o l , a n d also the optical activity ([aJD+4.4°) was the expected for a n 80% e.e. (reported [a] D +5.4°). 4 ) According to the stereochemistry of the reactions

4436

Joaquín R. MORAN, Victoria ALCAZAR, and Manuel GRANDE

[Vol. 61, No. 12

OH

10

11

R=H

11a R:CMe20Me

C6H5S

6 R=CHMeOBu 7 R=CMe2OMe

13

U

R:H

13a R: CMe20Me

R:H

U a R:CMe20Me

Chart 3.

a) 2,4-DNFB/NEt 3 , b) C 6 H 5 SH, K/EtOH, c) Ti(OPr) 4( (+)-DET, THBP/CH2CI2 - 2 0 ° C , d) BuO-CH=CH 2 or MeOCMe=CH 2 /TsOH, e) BuLi, DABCO/THF - 2 5 ° C , f) HC1 0.5 M, g) Li, NH 3 /Et 2 i\H.

a) i-BuOOH, VO(acac)2/C 6 H 6 , b) KOH/H2O, c) MeOCMe=CH 2 /C 6 H 6 (TsOH); BuLi, DABCO/THF - 2 5 ° C ; 4, d) Li, NH 3 /Et 2 NH. nendiol. Experimental

described, we consequently propose for c o m p o u n d 2 the absolute configuration 6S, 1R. However to rule o u t definitively the alternative stereochemistry, we repeated the reaction with the isomeric epoxide 11. T h e synthesis of this c o m p o u n d was accomplished starting from (—)-linalool, u s i n g ¿-butyl hydroperoxide a n d VO(acac) 2 , to get the e p o x i d a t i o n p r o d u c t 10. T h i s material rearranged cleanly into the trisubstituted epoxide 11 w h e n h a n d l e d with a q u e o u s KOH. 1 0 > Protection of the hydroxyl g r o u p w i t h methyl isopropenyl ether (11a), a n d reaction with the foregoing a n i o n 4, produced the expected epimeric m i x t u r e 12 w h i c h u p o n hydrolysis a n d desulfurization w i t h L i / N H 3 / E t 2 N H led to epipeucelinendiol 13 ([Q:]D — 7.5°) a n d its isomer with the disubstituted double b o n d 14. C o m p a r i s o n of the 1 3 C N M R spectra, specially the signals at 5-C (39.8 vs. 41.6), 7-C (49.6 vs. 47.7), 11-C (38.3 vs. 39.9), a n d 19-C (26.4 vs. 23.4) of epipeucelinendiol a n d the already described peucelinendiol, led n o d o u b t a b o u t their different structures. As a conclusion we propose the structure 2 for natural peuceli-

Optical rotations were measured on a polarimeter PerkinElmer 241. IR spectra were recorded on a Beckman Acculab II. NMR were recorded on a Bruker WP 200 SY (200 MHz l H, 50.3 MHz 13C). Protection of Geranyl Epoxide. The alcohol 5 (2.6 g), prepared as described in Ref. 9, was dissolved in ether (30 ml) and reacted with methyl isopropenyl ether or with butyl vinyl ether (5 ml) and a trace of TsOH. After 30 minutes at room temperature, ether and aqueous Na 2 C0 3 (4%) were added, the organic layer was dried and the solvent removed in vacuo to yield a crude material (3.2 g) which was used without further purification. 8-Phenylthiopeucelinendiol (8). The sulfide 4 (1.5 g), prepared as described in Ref. 6 in T H F (60 ml) and DABCO (750 mg) was cooled down to — 20 °C. An excess of BuLi (5 ml, 1.6 M in hexane; 1 M = l mol dm - 3 ) was then added. The reaction mixture turns then into orange. After 5 minutes, the epoxide 6 (or 7) was slowly dropped, and the mixture was allowed to warm up to room temperature. Work up, hydrolysis (0.5 M HC1) and chromatography on Si0 2 (60 g, hexane/ ether, 6:3) rendered 2.05 g (80%) of a 1:1 mixture of the epimeric hydroxy sulfides 8. lH NMR (CDC13) 5=7.30 (10H, m), 5.25 (6H, m), 4.10 (6H, m), 1.62 (6H,s), 1.60 (6H,s), 1.56 (6H, s), 1.52 (6H, s), 1.34 (3H, s), 0.95 (3H, s).

December, 1988]

Synthesis and Structure of the Diterpenoid Peucelinendiol

4437

Peucelinendiol (2) and Isopeucelinendiol (9). DesulfurizaI-CH3, I5-CH3), 25.5 (t, 12-C), 24.3 (q, 2CH 3 ), 22.4 (t, 4-C), tion of the foregoing mixture was carried out as follows: over 17.5 (q, I6-CH3, 2O-CH3), 16.2 (q, 17-CH3). the stirred sulfide mixture (380 mg) in diethylamine (3 ml), Epipeucelinendiol (13). The acetal 13a (110 mg) was hywas condensed NH 3 (30 ml). Li (100 mg) was added in small drolyzed in MeOH (8 ml; with aqueous HC1 (1 ml, 0.5 M) for pieces and the blue solution was kept at reflux temperature ten minutes. Work up with aqueous Na 2 C0 3 (4%), yielded 81 for 30 minutes. MeOH was then dropped in until the blue mg of the compound 13. Colorless oil. [«]D — 7.5° (c 0.8, color vanished and NH 3 was allowed to evaporate. Work up CHC13). IR (film) 3400, 2950, 1450, 1380, 1150, 1050, cm"1. with ether and aqueous HC1 (0.5 M) yielded a mixture (280 ' H N M R (CDC13) 6=5.05 (3H, m, 3-H, 9-H, 13-H), 3.75 (2H, mg) of two compounds which could be separated on a Si0 2 m, 18-H), 1.65 (6H, s, 1-CH3, 15-CH3), 1.58 (9H, s, I6-CH3, column (60 g, hexane/ether, 7 : 3) affording 175 mg of peuceI7-CH3, 2O-CH3), 1.26 (3H, 19-CH3). 1 3 CNMR (CDC13) linendiol 2 ([a] D +4.4° c 3, CHC13) and isopeucelinendiol 9 6=136.5 (s, 10-C), 131.8 (s, 2-C), 131.6 (s, 14-C), 124.5 (d, (60 mg), which showed the following physical data: \OL~\O 13-C), 124.3 (d, 3-C), 123.3 (d, 9-C), 76.2 (s, 6-C), 63.1 (t, -11.0° (c 3.3, CHCI3). IR (film) 3400, 2950, 1450, 1380, 1200, 18-C), 49.6 (d, 7-C), 39.8 (t, 5-C), 38.3 (t, 11-C), 26.7 (t, 8-C), 1040, 990 cm - 1 . *H NMR (CDC13) 6=5.37 (1H, dd / = 1 5 and 7 26.4 (q, 19-C), 25.6 (q, 1-C, 15-C), 25.3 (t, 12-C), 22.4 (t, 4-C), Hz, 9-H), 5.07 (1H, dd, / = 1 5 and 9 Hz, 8-H), 5.03 (2H, m, 17.6 (q, 16-C, 20-C), 16.1 (q, 17-C). 3-H, 13-H), 3.78 (1H, dd, / = 9 and 8 Hz, 18-HA), 3.55 (1H, dd, Epiisopeucelinendiol Acetal (14a). Oily, IR (film) 3400, / = 9 and 6 Hz, 18-HB), 2.35 (1H, m, 7-H), 1.60 (6H, s, 1-CH3, 2950, 1450, 1380, 1200, 1090, 980 cm"1. ' H N M R (CDC13) I5-CH3), 1.54 (3H, s, I6-CH3), 1.50 (3H, s, 20-CH3), 1.10 (3H, 5=5.05 (2H, m, 3-H, 13-H), 3.55 (2H, m, 18-H), 3.16 (3H, s, s, I9-CH3), 0.89 (3H, d, / = 7 Hz, 17-CH3). 13 CNMR (CDC13) OCH3), 1.63 (6H, s, I-CH3, I5-CH3), 1.57 (3H, s, 16-CH3), 6=140.9 (d, 8-C), 131.7 (s, 2-C), 131.2 (s, 14-C), 125.4 (d, 9-C), 1.54 (3H, s, 20-CH3), 1.30 (6H, s, 2 CH 3 ), 1.14 (3H, d, / = 7 Hz, 124.6 (d, 3-C), 124.5 (d, 13-C), 75.4 (s, 6-C), 64.2 (t, 18-C), 52.8 I7-CH3). 1 3 CNMR (CDCI3) 6=140.0 (d, 8-C), 131.1 (s, 2-C), (d, 7-C), 4.16 (t, 5-C), 37.1 (t, 11-C), 36.6 (d, 10-C), 25.8 (t, 131.0 (s, 14-C), 126.4 (d, 9-C), 100.3 (s, O-C-O), 74.0 (s, 6-C), 12-C), 25.6 (q, 1-C, 15-C), 23.5 (q, 19-C), 21.7 (t, 4-C), 20.6 (q, 63.0 (t, 18-C), 52.1 (q, OCH 3 ;, 48.7 (d, 7-C), 38.8 (t, 5-C), 37.2 17-C), 17.6 (q, 16-C, 20-C). (t, 11-C), 36.7 (d, 10-C), 25.9 (t, 12-C), 25.6 (q, 19-C), 25.5 (q, 1-C, 15-C), 24.3 (q, 2 CH 3 ), 22.1 (t, 4-C), 20.7 (q, 17-C), 17.6 8-(Phenylthio)epipeucelinendiol (12). The alcohol 11 (q, 16-C, 20-C). (710 mg) prepared according to Ref. 10, in ether (5 ml) was protected by reacting it with 2 ml of 2-methoxy propene and a trace of pyridinium tosylate during 10 minutes. Work up We w i s h to t h a n k Mr. A. Zarzo, U n i v e r s i t y of with aqueous Na 2 C0 3 (4%) and ether produced 750 mg of the Alicante, for the synthesis of 4 a n d Dr. Cambronero, epoxy acetal 11a which was used without purification in the ACEDESA, El P a l m a r , Murcia (Spain) for samples of next reaction. The sulfide 4 (500 mg) and DABCO (200 mg) geraniol a n d (—)-linalool. in T H F (20 ml) at — 20 °C were treated with BuLi in hexane (2 ml, 1.6 M). After 5 minutes the epoxy acetal 11a (400 mg) References in T H F (10 ml) was added and the reaction was allowed to warm up to room temperature. Usual work up followed by 1) J. de Pascual Teresa, C. Grande, and M. Grande, chromatography on Si0 2 (50 g, hexane/ether, 95 : 5) afforded Tetrahedron Lett, 1978, 4563. 650 mg of an epimeric sulfide mixture 12 which was further 2) J. de Pascual Teresa, C. Grande, J. R. Moran, and M. reacted by dissolving it in 6 ml of diethylamine and 50 ml of Grande, Chem. Lett., 1984, 247; J. de Pascual Teresa, J. R. refluxing NH 3 . Li (200 mg) was then added with strong Moran, J. J. Blanco, A. F. Mateos, and M. Grande, An. stirring and the reaction mixture was allowed to stand for 30 Quim., 82C, 183 (1986). minutes more. After this time MeOH was added until the 3) M. Soucek, V. Herout, and F. Sorm, Collect. Czech. blue color disappeared. Evaporation of the NH 3 and usual Chem. Commun., 26, 2551 (1961). work up with aqueous HC1 (0.5 M) and ether produced a 4) E. Lemmich, Photochemistry, 18, 1195 (1979). mixture (420 mg) which could be resolved on a Si0 2 column 5) L. Mangoni, D. Merola, P. Monaco, M. Parrilli, and (80 g, hexane/ether, 9:1) to yield epipeucelinendiol acetal L. Previtera, Tetrahedron Lett., 25, 2597 (1984). 13a (85 mg) and epiisopeucelinendiol acetal 14a (210 mg). 6) J. F. Biellmann and J. B. Ducep, Tetrahedron, 27, Epipeucelinendiol Acetal 13a. Oily, [a]D -11.0° (c 0.9, 5861 (1971). CHCI3). IR (firm) 3400, 2950, 1460, 1380, 1220, 1090, 1050 7) M. Kodama, Y. Matsuki, and S. Ito, Tetrahedron Lett., cm" 1 . *HNMR (CDC13) 6=5.10 (3H, m, 3-H, 9-H, 13-H), 1975, 3065. 3.55 (2H, m, 18-H), 3.16 (3H, s, OCH 3 ), 1.64 (6H, s, 1-CH3, 8) H. L. Goering and W. I. Kimoto, /. Am. Chem. Soc, I5-CH3), 1.57 (9H, s, I5-CH3, I7-CH3, 2O-CH3), 1.30 (3H, s, 87, 1748(1965). CH 3 ), 1.29 (3H, s, CH 3 ), 1.20 (3H, s, 19-CH3). 13 CNMR 9) T. Katsuki and K. B. Sharpless, / . Am. Chem. Soc, (CDCI3) 6=136.1 (s, 10-C), 131.3 (s, 2-C), 131.2 (s, 14-C), 124.9 102,5974(1980). (d, 3-C), 124.2 (d, 13-C), 123.5 (d, 9-C), 100.3 (s, O-C-O), 74.8 10) G. Ohloff, W. Giersch, K. H. Schulte-Elte, P. Enggist, (s, 6-C), 61.1 (t, 18-C), 48.8 (q, OCH 3 ), 47.9 (d, 7-C), 39.8 (t, and E. Demole, Helv. Chim. Acta, 63, 1582 (1980). 5-C), 38.6 (t, 11-C), 26.7 (t, 8-C), 25.9 (q, 19-CH3), 25.5 (q,